tbuckley/cabot-search huggingface dataset:
A global high-density chromatin interaction network reveals functional long-range and trans-chromosomal relationships
Authors: Ruchi Lohia, Nathan Fox, Jesse Gillis
Journal: Genome biology (2022)

Abstract Background Chromatin contacts are essential for gene-expression regulation; however, obtaining a high-resolution genome-wide chromatin contact map is still prohibitively expensive owing to large genome sizes and the quadratic scale of pairwise data. Chromosome conformation capture (3C)-based methods such as Hi-C have been extensively used to obtain chromatin contacts. However, since the sparsity of these maps increases with an increase in genomic distance between contacts, long-range or trans-chromatin contacts are especially challenging to sample. Results Here, we create a high-density reference genome-wide chromatin contact map using a meta-analytic approach. We integrate 3600 human, 6700 mouse, and 500 fly Hi-C experiments to create species-specific meta-Hi-C chromatin contact maps with 304 billion, 193 billion, and 19 billion contacts in respective species. We validate that meta-Hi-C contact maps are uniquely powered to capture functional chromatin contacts in both cis and trans. We find that while individual dataset Hi-C networks are largely unable to predict any long-range coexpression (median 0.54 AUC), meta-Hi-C networks perform comparably in both cis and trans (0.65 AUC vs 0.64 AUC). Similarly, for long-range expression quantitative trait loci (eQTL), meta-Hi-C contacts outperform all individual Hi-C experiments, providing an improvement over the conventionally used linear genomic distance-based association. Assessing between species, we find patterns of chromatin contact conservation in both cis and trans and strong associations with coexpression even in species for which Hi-C data is lacking. Conclusions We have generated an integrated chromatin interaction network which complements a large number of methodological and analytic approaches focused on improved specificity or interpretation. This high-depth “super-experiment” is surprisingly powerful in capturing long-range functional relationships of chromatin interactions, which are now able to predict coexpression, eQTLs, and cross-species relationships. The meta-Hi-C networks are available at https://labshare.cshl.edu/shares/gillislab/resource/HiC/ .
Personalized genome assembly for accurate cancer somatic mutation discovery using tumor-normal paired reference samples
Authors: Chunlin Xiao, Zhong Chen, Wanqiu Chen, Cory Padilla, Michael Colgan, Wenjun Wu, Li-Tai Fang, Tiantian Liu, Yibin Yang, Valerie Schneider, Charles Wang, Wenming Xiao
Journal: Genome biology (2022)

Abstract Background The use of a personalized haplotype-specific genome assembly, rather than an unrelated, mosaic genome like GRCh38, as a reference for detecting the full spectrum of somatic events from cancers has long been advocated but has never been explored in tumor-normal paired samples. Here, we provide the first demonstrated use of de novo assembled personalized genome as a reference for cancer mutation detection and quantifying the effects of the reference genomes on the accuracy of somatic mutation detection. Results We generate de novo assemblies of the first tumor-normal paired genomes, both nuclear and mitochondrial, derived from the same individual with triple negative breast cancer. The personalized genome was chromosomal scale, haplotype phased, and annotated. We demonstrate that it provides individual specific haplotypes for complex regions and medically relevant genes. We illustrate that the personalized genome reference not only improves read alignments for both short-read and long-read sequencing data but also ameliorates the detection accuracy of somatic SNVs and SVs. We identify the equivalent somatic mutation calls between two genome references and uncover novel somatic mutations only when personalized genome assembly is used as a reference. Conclusions Our findings demonstrate that use of a personalized genome with individual-specific haplotypes is essential for accurate detection of the full spectrum of somatic mutations in the paired tumor-normal samples. The unique resource and methodology established in this study will be beneficial to the development of precision oncology medicine not only for breast cancer, but also for other cancers.
Impact of poverty and neighborhood opportunity on outcomes for children treated with CD19-directed CAR T-cell therapy
Authors: Haley Newman, Yimei Li, Hongyan Liu, Regina M. Myers, Vicky Tam, Amanda DiNofia, Lisa Wray, Susan R. Rheingold, Colleen Callahan, Claire White, Diane Baniewicz, Lena E. Winestone, Stephan Kadauke, Caroline Diorio, Carl H. June, Kelly D. Getz, Richard Aplenc, David T. Teachey, Shannon L. Maude, Stephan A. Grupp, Kira Bona, Allison Barz Leahy
Journal: Blood (2022)
2022 American College of Rheumatology/EULAR classification criteria for Takayasu arteritis
Authors: Peter C Grayson, Cristina Ponte, Ravi Suppiah, Joanna C Robson, Katherine Bates Gribbons, Andrew Judge, Anthea Craven, Sara Khalid, Andrew Hutchings, Debashish Danda, Raashid A Luqmani, Richard A Watts, Peter A Merkel
Journal: Annals of the Rheumatic Diseases (2022)

Objective To develop and validate new classification criteria for Takayasu arteritis (TAK). Methods Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in six phases: (1) identification of candidate criteria items, (2) collection of candidate items present at diagnosis, (3) expert panel review of cases, (4) data‐driven reduction of candidate items, (5) derivation of a points‐based classification score in a development data set and (6) validation in an independent data set. Results The development data set consisted of 316 cases of TAK and 323 comparators. The validation data set consisted of an additional 146 cases of TAK and 127 comparators. Age ≤60 years at diagnosis and imaging evidence of large‐vessel vasculitis were absolute requirements to classify a patient as having TAK. The final criteria items and weights were as follows: female sex (+1), angina (+2), limb claudication (+2), arterial bruit (+2), reduced upper extremity pulse (+2), reduced pulse or tenderness of a carotid artery (+2), blood pressure difference between arms of ≥20 mm Hg (+1), number of affected arterial territories (+1 to +3), paired artery involvement (+1) and abdominal aorta plus renal or mesenteric involvement (+3). A patient could be classified as having TAK with a cumulative score of ≥5 points. When these criteria were tested in the validation data set, the model area under the curve was 0.97 (95% CI 0.94 to 0.99) with a sensitivity of 93.8% (95% CI 88.6% to 97.1%) and specificity of 99.2% (95% CI 96.7% to 100.0%). Conclusion The 2022 American College of Rheumatology/EULAR classification criteria for TAK are now validated for use in research.
Activating NO–sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury
Authors: Hao He, Wu Yang, Nan Su, Chuankai Zhang, Jianing Dai, Feng Han, Mahak Singhal, Wenjuan Bai, Xiaolan Zhu, Jing Zhu, Zhen Liu, Wencheng Xia, Xiaoting Liu, Chonghe Zhang, Kai Jiang, Wenhui Huang, Dan Chen, Zhaoyin Wang, Xueyang He, Frank Kirchhoff, Zhenyu Li, Cong Liu, Jingning Huan, Xiaohong Wang, Wu Wei, Jing Wang, Hellmut G. Augustin, Junhao Hu
Journal: The Journal of Experimental Medicine (2022)

Disruption of endothelial cell (ECs) and pericytes interactions results in vascular leakage in acute lung injury (ALI). However, molecular signals mediating EC–pericyte crosstalk have not been systemically investigated, and whether targeting such crosstalk could be adopted to combat ALI remains elusive. Using comparative genome-wide EC–pericyte crosstalk analysis of healthy and LPS-challenged lungs, we discovered that crosstalk between endothelial nitric oxide and pericyte soluble guanylate cyclase (NO–sGC) is impaired in ALI. Indeed, stimulating the NO–sGC pathway promotes vascular integrity and reduces lung edema and inflammation-induced lung injury, while pericyte-specific sGC knockout abolishes this protective effect. Mechanistically, sGC activation suppresses cytoskeleton rearrangement in pericytes through inhibiting VASP-dependent F-actin formation and MRTFA/SRF-dependent de novo synthesis of genes associated with cytoskeleton rearrangement, thereby leading to the stabilization of EC–pericyte interactions. Collectively, our data demonstrate that impaired NO–sGC crosstalk in the vascular niche results in elevated vascular permeability, and pharmacological activation of this crosstalk represents a promising translational therapy for ALI.
Genetic deletion and pharmacologic inhibition of E3 ubiquitin ligase HOIP impairs the propagation of myeloid leukemia
Authors: Koji Jimbo, Ayuna Hattori, Shuhei Koide, Takahiro Ito, Katsuhiro Sasaki, Kazuhiro Iwai, Yasuhito Nannya, Atsushi Iwama, Arinobu Tojo, Takaaki Konuma
Journal: Leukemia (2022)
Integrin β1 regulates marginal zone B cell differentiation and PI3K signaling
Authors: Virginia Andreani, Senthilkumar Ramamoorthy, Reinhard Fässler, Rudolf Grosschedl
Journal: The Journal of Experimental Medicine (2022)

Marginal zone (MZ) B cells represent innate-like B cells that mediate a fast immune response. The adhesion of MZ B cells to the marginal sinus of the spleen is governed by integrins. Here, we address the question of whether β1-integrin has additional functions by analyzing Itgb1fl/flCD21Cre mice in which the β1-integrin gene is deleted in mature B cells. We find that integrin β1–deficient mice have a defect in the differentiation of MZ B cells and plasma cells. We show that integrin β1–deficient transitional B cells, representing the precursors of MZ B cells, have enhanced B cell receptor (BCR) signaling, altered PI3K and Ras/ERK pathways, and an enhanced interaction of integrin-linked kinase (ILK) with the adaptor protein Grb2. Moreover, the MZ B cell defect of integrin β1–deficient mice could, at least in part, be restored by a pharmacological inhibition of the PI3K pathway. Thus, β1-integrin has an unexpected function in the differentiation and function of MZ B cells.
Avoiding Contrast-Enhanced Imaging to Prevent Contrast-Induced Acute Kidney Injury
Authors: Clement D. Lee, Jeremiah Hinson, Matthew S. Davenport
Journal: New England Journal of Medicine (2022)

This interactive feature about chronic kidney disease offers a case vignette accompanied by two essays, one supporting use of contrast-enhanced CT to diagnose pulmonary embolism and the other recommending avoiding it.
mTOR inhibition amplifies the anti-lymphoma effect of PI3Kβ/δ blockage in diffuse large B-cell lymphoma
Authors: Wendan Xu, Philipp Berning, Tabea Erdmann, Michael Grau, Nardjas Bettazová, Myroslav Zapukhlyak, Fabian Frontzek, Corinna Kosnopfel, Peter Lenz, Michael Grondine, Brandon Willis, James T. Lynch, Pavel Klener, Stephan Hailfinger, Simon T. Barry, Georg Lenz
Journal: Leukemia (2022)

Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease that exhibits constitutive activation of phosphoinositide 3-kinase (PI3K) driven by chronic B-cell receptor signaling or PTEN deficiency. Since pan-PI3K inhibitors cause severe side effects, we investigated the anti-lymphoma efficacy of the specific PI3Kβ/δ inhibitor AZD8186. We identified a subset of DLBCL models within activated B-cell–like (ABC) and germinal center B-cell–like (GCB) DLBCL that were sensitive to AZD8186 treatment. On the molecular level, PI3Kβ/δ inhibition decreased the pro-survival NF-κB and AP-1 activity or led to downregulation of the oncogenic transcription factor MYC. In AZD8186-resistant models, we detected a feedback activation of the PI3K/AKT/mTOR pathway following PI3Kβ/δ inhibition, which limited AZD8186 efficacy. The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3Kβ/δ inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kβ/δ signaling and thus identifies a previously unappreciated role of the PI3Kβ isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kβ/δ and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.
Clean Cooking Fuels to Improve Health during Pregnancy
Authors: Blair J. Wylie, Kwaku P. Asante
Journal: New England Journal of Medicine (2022)

Globally, approximately 3 billion people rely on solid biomass fuels such as crop residues or wood for cooking or heating.1 Household air pollution from incomplete combustion of these fuels is a mixture of fine particulate matter, carbon monoxide, and other substances and is associated with adverse health consequences, resulting in an estimated 2.3 million premature deaths annually.2 Included among the health risks attributable to household air pollution are low birth weight and pneumonia, which are key drivers of infant mortality in low-resource settings where the use of solid fuel is common. It is therefore with much anticipation that obstetricians, pediatricians, . . .
Race and Socioeconomic Bias in Pediatric Cardiac Transplantation
Authors: Shahnawaz Amdani, Jennifer Conway, Jake Kleinmahon, Scott Auerbach, Daphne Hsu, Melissa K. Cousino, Beth Kaufman, Juan Alejos, Jason Hopper Cruz, Hannah Y. Lee, Ramaraju Rudraraju, James K. Kirklin, Alfred Asante-Korang
Journal: JACC Heart Failure (2022)
The Joint Task Force on Practice Parameters GRADE guidelines for the medical management of chronic rhinosinusitis with nasal polyposis
Authors: Matthew A. Rank, Derek K. Chu, Antonio Bognanni, Paul Oykhman, Jonathan A. Bernstein, Anne K. Ellis, David B.K. Golden, Matthew Greenhawt, Caroline C. Horner, Dennis K. Ledford, Jay Lieberman, Amber U. Luong, Richard R. Orlandi, Shefali A. Samant, Marcus S. Shaker, Zachary M. Soler, Whitney W. Stevens, David R. Stukus, Julie Wang, Anju T. Peters
Journal: Journal of Allergy and Clinical Immunology (2022)
Single-cell genome-wide association reveals that a nonsynonymous variant in ERAP1 confers increased susceptibility to influenza virus
Authors: Benjamin H. Schott, Liuyang Wang, Xinyu Zhu, Alfred T. Harding, Emily R. Ko, Jeffrey S. Bourgeois, Erica J. Washington, Thomas W. Burke, Jack Anderson, Emma Bergstrom, Zoe Gardener, Suzanna Paterson, Richard G. Brennan, Christopher Chiu, Micah T. McClain, Christopher W. Woods, Simon G. Gregory, Nicholas S. Heaton, Dennis C. Ko
Journal: Cell Genomics (2022)
Hepatocyte-specific Mas activation enhances lipophagy and fatty acid oxidation to protect against acetaminophen-induced hepatotoxicity in mice
Authors: Shuai Chen, Zhi Lu, Haoyu Jia, Bo Yang, Chun Liu, Yuxin Yang, Shuo Zhang, Zhijing Wang, Liu Yang, Shanshan Li, Jing Li, Changqing Yang
Journal: Journal of Hepatology (2022)

Acetaminophen (APAP) is the most common cause of drug-induced liver injury (DILI); however, treatment options are limited. Mas is a G protein-coupled receptor whose role in APAP-induced hepatotoxicity has not yet been examined.Intrahepatic Mas expression was determined in both human and mouse DILI models. Mas1-/-, AlbcreMas1f/f, Ppara-/-, Mas1-/-Ppara-/- and wild-type mice were challenged with APAP for the in vivo analyses of Mas-AKT-FOXO1 axis-dependent lipophagy and fatty acid oxidation (FAO), using pharmacological compounds and genetic tools. Liver samples were collected for RNA-sequencing, proteomics, metabolomics, lipidomics, and metabolic flux analysis. Live-imaging of liver and histological, biochemical, and molecular studies were performed to evaluate APAP-induced hepatotoxicity in mice. Primary hepatocytes and hepatic cell lines were exposed to APAP for in vitro analysis.Intrahepatic Mas expression was significantly upregulated in human and mouse DILI models. Mice with systemic, liver-specific, or hepatocyte-specific Mas1 deficiency were vulnerable to APAP-induced hepatotoxicity. They exhibited substantially impaired lipophagy and downstream FAO, which was accompanied by the activation of AKT and suppression of FOXO1. In addition, the prophylactic activation of Mas conferred strong protection against APAP challenge in mice, with remarkably enhanced lipophagy and FAO dependent on the AKT-FOXO1 axis. Moreover, the protective effects of AVE0991 were substantially diminished by the inhibition of either lipophagy or FAO.The activation of Mas on hepatocytes enhanced AKT-FOXO1-dependent lipophagy and downstream FAO, protecting mice from APAP-induced hepatotoxicity and indicating that hepatocyte-specific Mas might be a novel therapeutic target for DILI.Mas signalling arises as a novel therapeutic target for patients with APAP-induced liver injury. The Mas-AKT/FOXO1-fatty acid degradation pathway could be critical for the development of treatment strategies for APAP overdose. When Mas signalling is targeted, the extent of liver injury should be considered at the time of administration. These findings obtained from APAP-challenged mice still need to be confirmed in a clinical context.
Efficacy and safety of oral ritlecitinib for the treatment of active nonsegmental vitiligo: A randomized phase 2b clinical trial
Authors: Khaled Ezzedine, Elena Peeva, Yuji Yamaguchi, Lori Ann Cox, Anindita Banerjee, George Han, Iltefat Hamzavi, Anand K. Ganesan, Mauro Picardo, Diamant Thaçi, John E. Harris, Jung Min Bae, Katsuhiko Tsukamoto, Rodney Sinclair, Amit G. Pandya, Abigail Sloan, Dahong Yu, Kavita Gandhi, Michael S. Vincent, Brett King
Journal: Journal of the American Academy of Dermatology (2022)
Lysophosphatidylcholines modulate immunoregulatory checkpoints in peripheral monocytes and are associated with mortality in people with acute liver failure
Authors: Francesca M Trovato, Rabiya Zia, Florent Artru, Salma Mujib, Ellen Jerome, Anna Cavazza, Muireann Coen, Ian Wilson, Elaine Holmes, Phillip Morgan, Arjuna Singanayagam, Christine Bernsmeier, Salvatore Napoli, William Bernal, Julia Wendon, Rosa Miquel, Krishna Menon, Vishal C Patel, John Smith, Stephen R Atkinson, Evangelos Triantafyllou, Mark J W McPhail
Journal: Journal of Hepatology (2022)

Acute liver failure (ALF) is a life-threatening disease characterised by high-grade inflammation and immunoparesis, which is associated with a high incidence of death from sepsis. Herein, we aimed to describe the metabolic dysregulation in ALF and determine whether systemic immune responses are modulated via the lysophosphatidylcholine (LPC)-autotaxin (ATX)-lysophosphatidylcholinic acid (LPA) pathway.
Prediction of Left Ventricular Reverse Remodeling and Outcomes by Circulating Collagen-Derived Peptides
Authors: Susana Ravassa, Josep Lupón, Begoña López, Pau Codina, Mar Domingo, Elena Revuelta-López, María U. Moreno, Gorka San José, Evelyn Santiago-Vacas, Germán Cediel, Carmen Roncal, Javier Díez, Antoni Bayés-Genís, Arantxa González
Journal: JACC Heart Failure (2022)
IGFBP-7 and Outcomes in Heart Failure With Reduced Ejection Fraction
Authors: Carly Adamson, Paul Welsh, Kieran F. Docherty, Rudolf A. de Boer, Mirta Diez, Jarosław Drożdż, Andre Dukát, Silvio E. Inzucchi, Lars Køber, Mikhail N. Kosiborod, Charlotta E.A. Ljungman, Felipe A. Martinez, Piotr Ponikowski, Marc S. Sabatine, David A. Morrow, Daniel Lindholm, Ann Hammarstedt, David W. Boulton, Peter J. Greasley, Anna Maria Langkilde, Scott D. Solomon, Naveed Sattar, John J.V. McMurray, Pardeep S. Jhund
Journal: JACC Heart Failure (2022)

Insulin-like growth factor–binding protein-7 (IGFBP-7) has been proposed as a potential prognostic biomarker in heart failure (HF), but the association between elevation in IGFBP-7 and HF outcomes in ambulant patients with heart failure with reduced ejection fraction (HFrEF) is unknown. The authors addressed this question in a post hoc analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. The primary outcome was a composite of cardiovascular death or a worsening HF event. The risk of adverse outcome was compared across tertiles of IGFBP-7 concentration by means of Cox proportional hazard models adjusted for N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT). The efficacy of randomized treatment across IGFBP-7 tertiles was assessed. Change in IGFBP-7 at 12 months was compared with the use of geometric means. A total of 3,158 patients had IGFBP-7 measured at baseline, and 2,493 had a repeated measure at 12 months. Patients in the highest tertile of IGFBP-7 had evidence of more advanced HFrEF. The adjusted HR for the primary endpoint in tertile 3, compared with tertile 1, was 1.48 (95% CI: 1.17-1.88). There was no modification of the benefit of dapagliflozin by baseline IGFBP-7 (P interaction = 0.34). Dapagliflozin did not change IGFBP-7 levels over 1 year (P = 0.34). Higher IGFBP-7 in patients with HFrEF was associated with worse clinical profile and an increased risk of adverse clinical outcomes. IGFBP-7 provided prognostic information incremental to clinical variables, NT-proBNP, and hsTnT. The benefit of dapagliflozin was not modulated by IGFBP-7 level. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124)
Prediction of Left Ventricular Ejection Fraction Change Following Treatment With Sacubitril/Valsartan
Authors: Reza Mohebi, Yuxi Liu, G. Michael Felker, Margaret F. Prescott, Ileana L. Piña, Javed Butler, Jonathan H. Ward, Scott D. Solomon, James L. Januzzi
Journal: JACC Heart Failure (2022)

Sacubitril/valsartan (Sac/Val) improves left ventricular ejection fraction (LVEF) in heart failure (HF) with reduced ejection fraction regardless of previous treatments. Improvements in LVEF may change eligibility for primary implantable cardioverter-defibrillator (ICD) placement. Awaiting LVEF improvement may expose patients to potential risks for arrhythmic complications. The authors sought to develop a model predicting LVEF change after Sac/Val therapy. A total of 416 persons with HF and LVEF of <35% were included in this analysis. Following initiation of Sac/Val, echocardiographic parameters were measured serially for 1 year. A machine learning algorithm was implemented to develop a risk model for predicting the persistence of LVEF of <35% after 1 year and was validated in a separate group of study participants. Baseline LVEF, left ventricular mass index, HF duration, age, N-terminal pro–B-type natriuretic peptide concentration at baseline and change by day 14, and body mass index were the most significant factors for identifying lack of LVEF improvement to ≥35% after 1 year. In the training and validation cohorts, the areas under the model curve for predicting lack of LVEF improvement were 0.92 and 0.86, respectively. Three categories of likelihood for LVEF of <35% after 1 year of Sac/Val treatment were developed based on the model predictions: 3.8%, 30.1%, and 83.7%. During follow-up, arrhythmia event rates were 0.9%, 2.9%, and 6.7% in these groups, respectively. Many persons with HF with reduced ejection fraction eligible for ICD insertion experience an increase in LVEF to ≥35% after treatment with Sac/Val. Early identification of those less likely to improve their LVEF might allow for more refined selection of primary ICD candidates. (Effects of Sacubitril/Valsartan Therapy on biomarkers, Myocardial Remodeling, and Outcomes [PROVE-HF]; NCT02887183)